Idiopathic Pulmonary Fibrosis (IPF) is a lethal fibrotic lung disorder that kills 40,000 Americans each year and over 1 million persons worldwide. In IPF, relentless expansion and alteration of the alveolar mesenchymal cell population leads to production of diseased myofibroblasts that mediate progressive scarring of the gas exchange surface resulting in death by asphyxiation. Fibroblasts derived from the lungs of IPF patients have phenotypic hallmarks that distinguish them from their normal counterparts. IPF fibroblasts have altered integrin expression, are hyperproliferative, produce increased amounts of collagen, express increased amounts of ?mooth muscle actin (?MA) and form fibrotic lesions in model organisms. We recently published that pathological lung mesenchymal progenitor cells (MPCs) are a cell-of-origin for the IPF fibroblast; and that IPF extracellular matrix (ECM) reprograms fibroblast gene expression to establish a positive feedback loop that translationally activates ECM genes and their cognate cell surface receptors. In this project we summarize our paradigm-shifting data. First, we show that IPF lungs MPCs - but not control lung MPCs - generate progeny with the in vitro and in vivo hallmarks of IPF fibroblasts. Next, we show that when primary lung fibroblasts (IPF or control) interact with decellularized lung ECM (IPF or control): i) the ECM source predominantly dictates gene expression; ii) IPF lung ECM translationally activates ECM genes and genes encoding their cognate integrin receptors; and iii) IPF lung ECM, but not control ECM, decreases fibroblast expression of miR29 - a potent negative regulator of ECM and proliferation genes - creating a positive feedback loop that provides a molecular mechanism for relentless disease progression. Based on this, we hypothesize that decellularized IPF lung ECM will direct human lung MPC differentiation towards the IPF phenotype; and stabilize that phenotype by epigenetic regulation of miR29 expression to create a positive feedback loop driving genes governing IPF fibroblast hallmarks. We propose 2 specific aims to elucidate the molecular mechanisms. Specific Aim 1: Genesis of the IPF fibroblast - Characterize the mechanisms by which MPCs acquire IPF phenotypic hallmarks on IPF lung ECM. Specific Aim 2: Disease Progression - Dissect the molecular and cellular mechanisms of the IPF ECM-driven positive feedback loop that increases integrin and ECM gene expression and suppresses their negative regulator, miR29. If we achieve our aims, our work will unveil mechanisms governing the genesis, maintenance and propagation of the IPF fibroblast and its pathological ECM. This information is foundational for developing therapies that target those ECM - mesenchymal cell interactions that drive IPF.